Neonatal diabetes mellitus is a rare form of insulin dependent
diabetes mellitus that present within the first month of life, lasting
at least two weeks and requiring insulin therapy. Intrauterine growth
restriction, failure to thrive, fever, dehydration, hyperglycemia and
acidosis with or without ketonuria are the clinical features of the
disease. We report four cases of neonatal diabetes mellitus; two of
them had a transient course.

Key words: Insulin, Neonatal Diabetes mellitus

Impaired glucose tolerance in neonates can be due
to various factors including neonatal diabetes mellitus (NDM).
Neonatal diabetes mellitus is a rare form of insulin dependent
diabetes mellitus (IDDM) with an incidence of 1/400 000 that present
within the first four weeks of life persisting for at least two weeks
and requiring insulin treatment(1,2). The outcome is highly variable;
may be either permanent, or transient with/without subsequent
recurrence(3). We present four cases of neonatal diabetes mellitus;
two of them had a transient course.

Case Reports

Case 1

This term male neonate was the fourth child of non-consanguinous
parents. The mother was 38 years old and pregnancy was complicated by
severe oligohydramnios. His birth weight was 1860 g (<10th percentile)
and length was 32 cm (10-25th percentile). The physical examination was
normal. His brother had been diagnosed as IDDM when he was five years
old.

On the 10th day of hospitalization, he had
hyperglycemia (307 mg/dL) and was treated with subcutaneous crystalline
insulin because of persistent high glucose levels. He was fed eight
times a day with 120 kcal/kg/day. During hospitalization, he sometimes
developed metabolic acidosis without ketosis requiring bicarbonate
therapy. On the 26th day, subcutaneous isophane (NPH) insulin was
started once daily. His insulin and C-peptide levels were 2.2 micCIU/mL
(normal values 2.1-30.8 micIU/mL) and 0.2 ng/mL (normal values 1.1-3.2
ng/mL) respectively. Tests for intrauterine infections (TORCH) and islet
cell antibodies were negative. He gained 30-50 g/kg/day of weight during
hospitalization. On 44th day of hospitalization he was discharged on
twice daily insulin regimen. However, his parents gave up insulin
treatment after discharge and on follow up at 3 months of age he was
well and his blood glucose levels were within normal limits. He is now 3
years old and a well growing child.

Case 2

This female neonate was the first child of young
consanguinous parents. Pregnancy was complicated by oligohydramnios and
cesarean section was performed at 36 week gestation age. Her birth
weight was 1200 g (<10th percentile) and length was 34 cm (<10th
percentile). The physical examination was normal. Her grandmother and
grand aunt have non-insulin dependent diabetes mellitus. On the 3rd day
of life she had hyperglycemia (380 mg/dL) and was treated with
subcutaneous insulin (0.1 U/kg). Her insulin and C-peptide levels were
low, 2 micIU/mL and 0.1 ng/mL respectively. Intrauterine infection
markers and islet cell antibodies were negative, HbAlc levels were
normal. Between day 4 and 10 of life, she remained normoglycemic and did
not require insulin treatment. Glucose levels were between 65-117g/dL.
After 10th day of life, hyperglycemia reccured and insulin infusion
(0.1-0.5 U/kg/h) was started.

Blood ketones were negative at hyperglycemic periods
and she never developed acidosis. After 30 days, NPH insulin treatment
was started. During treatment she had hypoglycemia with blood glucoce
levels between 25-45 mg/dL and treated with enteral or parenteral
glucose. She gained 30-60 g/kg/day with eight times feeding per day. She
is now 2 years of age and on insulin glarjin 2 times a day. Her blood
glucose and glycosy-lated hemoglobin levels are under control.

Case 3

The infant was a term, small for gestational age,
male infant of consanguinous parents, admitted at 18 days of age. His
growth parameters were 2250 g body weight (<10th percentile) and 50 cm
length (50-75th percentile). On admission, he was in respiratory
distress, acidotic, dehydrated and septic in appearance. Laboratory
investigations demonstrated hyperglycemia (390 mg/dL),
hypertriglyceridemia, severe metabolic acidosis, renal failure, and
hypernatremia. His C-peptide level was 0.9 ng/mL. The problems were
resolved with appropriate therapy and persistent hyperglycemia was
treated with continuous intravenous (0.1.-0.7 U/kg/h) and subsequent
subcutaneous insulin therapy. The insulin treatment was discontinued at
4 months of age. He is now 14 months old and blood glucose values are in
normal range.

Case 4

This male infant was born severely growth retarded at
36 weeks of gestation to a gestationally diabetic mother. The parents
were consanguinous. He was referred at 5 days of age for persistent
hyperglycemia (410 and 380 mg/dL). His growth related parameters were
1300 g body weight (<10th percentile), 38 cm length (<10th percentile),
and 29 cm head circumference (<10th percentile). On physical
examination, he was not acidotic, had no clinical manifestations of
hyperglycemia and dysmorphic features were not detected. He was treated
with insulin but glucose control was erratic. Plasma C-peptide level was
0.57 ng/mL, insulin was 0.17 micIU/mL, islet-cell antibodies were
negative and his glycosylated hemoglobin values were elevated. He is now
2½-years-old and on insulin glarjin once a day. He has good glycemic
control but poor weight gain.

Discussion

Hyperglycemia, defined as fasting blood glucose
greater than 125 mg/dL is mostly seen in very low birth weight infants
receiving intravenous glucose infusion. Sepsis and stress can also be
associated with hyperglycemia by catecholamines, cortisol influences on
the mobilization of glycogen, gluconeogenesis and insulin response. On
the other hand, endotoxins may have a direct effect on insulin actions
in septic infants. Transient and permanent diabetes mellitus have to be
differentiated from the transient hyper-glycemia seen in neonates
receiving parenteral glucose infusion and those with septicemia and
central nervous system disorders(2). All of our patients were healthy,
were not receiving parenteral nutrition and sepsis markers were
negative.

Neonatal diabetes mellitus, an uncommon cause of
hyperglycemia in the newborn period, presents within the first four
weeks of life and persists for more than two weeks(3). Intrauterine
growth retardation, failure to thrive, fever, dehydration,
hyperglycemia, acidosis with or without ketonuria are the clinical
features of the disease. Insulin secreted by the fetal pancreas has a
significant role in growth and metabolism of the fetus during the last
half of gestation. Intrauterine deficiency of insulin may be the cause
of intrauterine growth retardation(4). All the patients reported here
had intrauterine growth retardation and had low levels of insulin and
C-peptide.

Etiology of NDM is unclear and its pathogenesis
differs from insulin dependent diabetes mellitus in childhood because of
its highly variable course. Presence of islet cell antibodies has not
been reported in NDM(5). Absence of autoimmune markers typical for IDDM
is also consistent with the diagnosis(4). Islet cell antibodies of the
present patients were negative.

Neonatal diabetes mellitus, seems to form a distinct
entity of inborn pancreatic mal-function(4). First phase of insulin
release during the intravenous glucose tolerance test is a sensitive
index of beta cell reserve; if there is a decreased first phase of
insulin response, this is a good predictor of later development of
diabetes mellitus(6). Most children with transient NDM in remission have
no evidence of beta cell dysfunction or insulin resistance in the
fasting state(7). In a study about half of the NDM patients developed
permanent diabetes mellitus(3). Of the patients reported by von
Muhlendahl, 26 infants had permanent diabetes, 18 had transient
diabetes, and 13 had transient which diabetes recurred when they were 7
to 20 years old(3). Permanent NDM developed in 2 of the patients
reported here.

Transient neonatal diabetes mellitus (TNDM) typically
lasts for weeks and months requiring insulin therapy(8). Most of the
cases of TNDM are sporadic but there are familial cases(9). Although
they often have a permanent remission, they need to be closely followed
as diabetes can recur(3). Several hypothesis concerning its etiology
have been postulated, such as pancreatic immaturity, paternal
uniparental isodisomy of chromo-some 6 and the existence of a gene
located in 6q22-23 chromosome region subjected to imprinting and
exclusively of paternal expression(10-13). Unfortunately, paternal
uniparental isodisomy could not be studied in these patients.

The cause of b-cell destruction in permanent
cases is not yet known. Permanent NDM is uncommon and is usually due to
a pancreatic dysgenesis often associated with other malformations
(3,14-16). Giralt, et al.(15) described permanent diabetes of a
neonate with hypothyroidism, bilateral sensorineural deafness, and
bilateral congenital cataract. Kentrup, et al.(16) described a
case of NDM with hyper-galactosemia and Milenkovic, et al.(17)
reported macroglossia, umbilical hernia, onychomycosis, inguinoscrotal
hernia with TNDM. Our patients did not have any associated anomaly. The
prognosis is different in transient and permanent forms and it is
difficult to distinguish these forms at onset.

In conclusion, NDM should be considered in the
diagnosis of hyperglycemic and small for date infants. Close blood
glucose monitoring is essential as long as hyperglycemia persists.
Because recurrent diabetes is common in patients with transient NDM,
prolonged follow up is imperative

Contributors: All authors were involved in
management of cases, search of literature and writing the manuscript.